Our hypothesis is that arterioles are the principal suppliers of oxygen to skeletal muscle at rest and connective tissue, and that a substantial fraction of the oxygen delivered to the tissue by the arterioles is used by the arteriolar vessel wall. High oxygen consumption by the arteriolar wall/endothelium/smooth muscle causes the presence of large oxygen gradients next to the blood tissue interface. These gradients determine the high rate of oxygen exit from arterioles by diffusion a phenomenon measured by other investigators using oxygen microelectrodes and the change in microvessel blood oxygen saturation and by us using the phosphorescence quenching technique. The rate of oxygen consumption by the arteriolar microvascular wall may account for as much as 30% of total oxygen use by some tissues, a phenomenon also found in whole organ studies by others. Our hypothesis is that arteriolar wall oxygen consumption is increased by vasoconstriction, low shear stress at the blood-endothelium interface, and decreased NO availability which lowers tissue oxygenation. Conversely the opposite effects lower oxygen consumption by the arteriolar wall and increase tissue oxygen. An additional mechanism is that NO curbs or minimizes oxygen consumption of the vessel wall and acts as a brake to oxygen consumption. It is proposed that blood viscosity is a determinant of p02 distribution in the microcirculation because: 1) Viscosity is a factor in determining peripheral vascular resistance, blood flow and perfusion; 2) The rate of oxygen exit from the microvessels is the balance between flow velocity and outward diffusion; and, 3) Blood viscosity determines the release of endothelial derived prostaglandin and NO via wall shear stress mediated mechanisms. These mechanisms directly affect functional capillary density, which is a determinant of tissue survival even though capillaries provide minimal oxygen to the tissue. The methods comprise in vivo measurements of microvascular transport properties including micro-p02 and micro-NO measurements in blood and tissue, blood flow velocity, functional capillary density and arteriolar reactivity. Our investigations use the method of mass balance to predict the vessel wall oxygen consumption needed to explain the rate of oxygen exit from the arterioles, and the high resolution phosphorescence quenching oxygen measurement technique to experimentally verify the theoretical predictions. Our research aims at advancing our understanding of tissue oxygenation and provides a new conceptual framework with which to analyze the ischemic process.